Inhibitors of 11-beta-hydroxy steroid dehydrogenase type 1

ABSTRACT

The present invention relates to using a compound having the formula (I) wherein T is I) thienyl, which optionally is substituted with halogen, or II) phenyl optionally substituted with halogen and/or C 1-6 -alkyl; E is a bond, —CH 2 — or —CO—; L is a bond, —CH 2 —, —CHR 4 — or —NR 3 —; R 3  is H, C 1-6 -alkyl, C 1-6 -acyl or —COR 4 ; R 4  is morpholino or C 1-6 -amido; R 6  and R 7  are independently hydrogen or C 1-6 -alkyl; and R 8  and R 9  are independently hydrogen or C 1-6 -alkyl, as well as pharmaceutically acceptable salts, hydrates and solvates thereof, in the manufacture of a medicament for the treatment or prevention of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis, tuberculosis, dementia, depression, virus diseases and inflammatory disorders.

TECHNICAL FIELD

[0001] The present invention relates to novel compounds, topharmaceutical compositions comprising the compounds, to processes fortheir preparation, as well as to the use of the compounds in medicineand for the preparation of a medicament which acts on the human11-β-hydroxysteroid dehydrogenase type 1 enzyme (11βHSD1).

BACKGROUND ART

[0002] 1. Glucorticoids, Diabetes and Hepatic Glucose Production

[0003] It has been known for more than half a century thatglucocorticoids have a central role in diabetes, e.g. the removal of thepituitary or the adrenal gland from a diabetic animal alleviates themost severe symptoms of diabetes and lowers the concentration of glucosein the blood (Long, C. D. and F. D. W. Leunins (1936) J. Exp. Med.63:465-490; Houssay, B. A. (1942) Endocrinology 30:884-892). It is alsowell established that glucocorticoids enable the effect of glucagon onthe liver.

[0004] The role of 11βHSD1 as an important regulator of localglucocorticoids effect and thus of hepatic glucose production is wellsubstantiated (see e.g. Jamieson et al. (2000) J. Endocrinol. 165: p.685-692). The hepatic insulin sensitivity was improved in healthy humanvolunteers treated with the non-specific 11βHSD1 inhibitor carbenoxolone(Walker, B. R et al. (1995) J. Clin. Endocrinol. Metab. 80:3155-3159).Furthermore, the expected mechanism has been established by differentexperiments with mice and rats. These studies showed that the MRNAlevels and activities of two key enzymes in hepatic glucose productionwere reduced, namely: the rate-limiting enzyme gluconeogenesis,phosphoenolpyrnvate carboxykinase (PEPCK), and glucose-6-phosphatase(G6Pase) catalyzing the last common step of gluconeogenesis andglycogenolysis. Finally, the blood glucose level and hepatic glucoseproduction is reduced in mice having the 11βHSD1 gene knocked-out. Datafrom this model also confirm that inhibition of 11βHSD1 will not causehypoglycemia, as predicted since the basal levels of PEPCK and G6Paseare regulated independently of glucocorticoids (Kotelevtsev, Y. et al.,(1997) Proc. Natl. Acad. Sci. USA 94:14924-14929).

[0005] 2. Possible Reduction of Obesity and Obesity RelatedCardiovascular Risk Factors

[0006] Obesity is an important factor in syndrome X as well as in themajority (>80%) of type 2 diabetic, and omental fat appears to be ofcentral importance. Abdominal obesity is closely associated with glucoseintolerance, hyperinsulinemia, hypertiglycefidemia, and other factors ofthe so-called syndrome X (e.g. raised blood pressure, decreased levelsof IDL and increased levels of VLDL) (Montague & O'Rahilly, Diabetes49:883-888, 2000). Ihiibition of the enzyme in pre-adipocytes (stromalcells) has been shown to decrease the rate of differentiation intoadipocytes. This is predicted to result in dimniliished expansion(possibly reduction) of the omental fat depot, i.e. reduced centralobesity (Bujalska, I. J., S. Kumar, and P. M. Stewart (1997) Lancet349:1210-1213).

[0007] Inhibition of 11βHSD1 in mature adipocytes is expected toattenuate secretion of the plasminogen activator inhibitor 1 (PAI-1)—anindependent cardiovascular risk factor (Halleux, C. M. et al. (1999) J.Clin. Endocrinol. Metab. 84:4097-4105). Furthermore, there is a clearcorrelation between glucocorticoid “activity” and cardiovascular riskfactor suggesting that a reduction of the glucocorticoid effects wouldbe beneficial (Walker, B. R et al. (1998) Hypertension 31:891-895;Fraser, R. et al. (1999) Hypertension 33:1364-1368).

[0008] Adrenalectomy attenuates the effect of fasting to increase bothfood intake and hypothalamic neuropeptide Y expression. This supportsthe role of glucocorticoids in promoting food intake and suggests thatinhibition of 11βHSD1 in the brain might increase satiety and thereforereduce food intake (Woods, S. C. et al. (1998) Science, 280:1378-1383).

[0009] 3. Possible Beneficial Effect on the Pancreas

[0010] Inhibition of 11βHSD1 in isolated urine pancreatic 13-cellsimproves the glucose-stimulated insulin secretion (Davani, B. et al.(2000) J. Biol. Chem. Nov 10, 2000; 275(45):34841-4). Glucocorticoidswere previously known to reduce pancreatic insulin release in vivo(illaudel, B. and B. C. J. Sutter (1979) Horm. Metab. Res. 11:555-560).Thus, inhibition of 11βHSD1 is predicted to yield other beneficialeffects for diabetes treatment, besides effects on liver and fat.

[0011] 4. Possible Beneficial Effects on Cognition and Dementia

[0012] Stress and glucocorticoids influence cognitive function (deQuervain, D. J.-F., B. Roozendaal, and J. L. McGaugh (1998) Nature394:787-790). The enzyme 11βHSD1 controls the level of glucocorticoidaction in the brain and thus contributes to neurotoxicity (Rajan, V., C.R. W. Edwards, and J. R Secki, J. (1996) Neuroscience 16:65-70; Seckl,J. R-, Front. (2000) Neuroendocrinol. 18:49-99). Unpublished resultsindicate significant memory improvement in rats treated with anon-specific 11βHSD1 inhibitor (J. Seckl, personal communication). Basedthe above and on the known effects of glucocorticoids in the brain, itmay also be suggested that inhibiting 11βHSD1 in the brain may result inreduced arriety (Tronche, F. et al. (1999) Nature Genetics 23:99-103).Thus, taken together, the hypothesis is that inhibition of 11βHSD1 inthe human brain would prevent reactivation of cortisone into cortisoland protect against deleterious glucocorticoid-mediated effects onneuronal survival and other aspects of neuronal function, includingcognitive impairment, depression, and increased appetite (previoussection).

[0013] 5. Possible Use of Immuno-Modulation Using 11βHSD1 Inhibitors

[0014] The general perception is that glucocorticoids suppress theimmune system. But in fact there is a dynamic interaction between theimmune system and the HPA hypothalamo-pitaitary-adrenal) axis (Rook, G.A. W. (1999) Baillièr's Clin. Endocrinol. Metab. 13:576-581). Thebalance between the cell-mediated response and humoral responses ismodulated by glucocorticoids. A high glucocorticoid activity, such as ata state of stress, is associated with a humoral response. Thus,inhibition of the enzyme 11βHSD1 has been suggested as a means ofshifting the response towards a cell-based reaction.

[0015] In certain disease states, including tuberculosis, lepra andpsoriasis the immune reaction is normally biased towards a humoralresponse when in fact the appropriate response would be cell based.Temporal inhibition of 11βHSD1, local or systemic, might be used to pushthe immune system into the appropriate response (Mason, D. (1991)Immunology Today 12. 57-60; Rook et al., supra).

[0016] An analogous use of 11βHSD1 inhibition, in this case temporalwould be to booster the immune response in association with immunizationto ensure that a cell based response would be obtained, when desired

[0017] 6. Reduction of Intraocular Pressure

[0018] Recent data suggest that the levels of the glucocorticoid targetreceptors and the 11βHSD enzymes determines the susceptibility toglaucoma (Stokes, J. et al. (2000) Invest. Ophthalmol. 41:1629-1638).Further, inhibition of 11βHSD1 was recently presented as a novelapproach to lower the intraocular pressure (Walker E. A. et al, posterP3-698 at the Endocrine society meeting Jun. 12-15, 1999, San Diego).Ingestion of carbenoxolone, a non-specific inhibitor of 11βHSD1, wasshown to reduce the intraocular pressure by 20% in normal subjects. Inthe eye, expression of 11βHSD1 is confined to basal cells of the cornealepithelium and the

epithelialium of the cornea (the site of aqueous production), toculinary muscle and to the sphincter and dilator muscles of the iris. Incontrast, the distant isoenzyme 11βHSD2 is highly expressed in thenon-pigmented ciliary epithelinm and corneal endothelium. None of theenzymes is found at the trabecular meshwork, the site of drainage. Thus,11βHSD1 is suggested to have a role in aqueous production, rather thandrainage, but it is presently unknown if this is by interfering withactivation of the glucocorticoid or the mineralocorticoid receptor, orboth.

[0019] 7. Reduced Osteoporosis

[0020] Glucocorticoids have an essential role in skeletal developmentand function but are detrimental in excess. Glucocorticoid-induced boneloss is derived, at least in part via inhibition of bone formation,which includes suppression of osteoblast proliferation and collagensynthesis (Kim, C. H., S. L. Cheng, and G. S. Kim (1999) J. Endocrinol.162:371-379). The negative effect on bone nodule formation could beblocked by the non-specific inhibitor carbenoxolone suggesting animportant role of 11βHSD1 in the glucocorticoid effect (Bellows, C. G.,A. Ciaccia, and J. N. M. Heersche, (1998) Bone 23:119-125). Other datasuggest a role of 11βHSD1 in providing sufficiently high levels ofactive glucocorticoid in osteoclasts, and thus in augmenting boneresorption (Cooper, M. S. et al. (2000) Bone 27:375-381). Takentogether, these different data suggest that inhibition of 11βHSD1 mayhave beneficial effects against osteoporosis by more than one mechanismworking in parallel.

[0021] WO 99/65884 discloses carbon subtituted aminothiazole inhibitorsof cyci dependent kinases. These compounds may e.g. be used againstcancer, inflammation and arthritis. U.S. Pat. No. 5,856,347 discloses anantibacterial preparation or bactericide comprising 2-aminothiazolederivative and/or salt thereof. Further, U.S. Pat. No. 5,403,857discloses benzenesulfonamide derivatives having 5-lipoxygenaseinhibitory activity. Additionally, tetrahydrothiazolo[5,4-c]pyridinesare disclosed in: Analgesic tetrahydrothiazolo[5,4-c]pyridines. Fr.Addn. (1969), 18 pp, Addn. to Fr. 1498461. CODEN: FAXXA3; FR 9412319690704 CAN 72:100685 AN 1970:100685 CAPLUS and4,5,6,7-Tetrahydroiiaolo[5,4-c]pyridines. Neth. Appl. (1967), 39 pp.CODEN:NAXXAN NL 6610324 19670124 CAN 68:49593, AN 1968:49593 CAPLUS.

[0022] FR 2384498 discloses thiazolo-benzenesulfonamides which showantibacterial anffmgal and hypoglycaemic properties. WO99/28306 and EP 0819 681 A2 relate to thiazolobenzenesulfonamides which can be used fortreating neurodegenerative pathologies, such as Alzheimer's disease. JP7149745 A2 and JP 7149746 A2 both describe 2-aminothiazole derivativesas esterase inhibitors. Nothing is disclosed about inhibiting 11βHSD1.JP 7309757 A2 relates to treating Alzheimer's disease usingN-(5-nitro-2-thiazolyl)benzenesulfonamides. JP 3173876 A2 presentspreparation of diphenylthiazoles. These compounds are used asanti-inflammatores, analgesics, anti-allergy agents, uric acidaccelerators and blood platelet aggregation inhibitors. EP 0 790 057 A1discloses an antibacterial or bactericide comprising a 2-aminothiazolederivative. U.S. Pat. No. 2,362,087 describes the preparation ofthiazolobenzenesulfonamides, such as2-bromobenzenesulfonamido4-methylthiazole. Nothing is disclosed aboutinhibiting 11βHSD1 and no therapeutic use of such substances isdisclosed.

[0023] However, none of the above disclosures discloses the compoundsaccording to the present invention, or their use for the treatment ofdiabetes, obesity, glaucoma, osteoporosis, cognitive disorders, =imunedisorders, and depression.

[0024] Consequently, there is a need of new compounds that are useful inthe treatment of diabetes, obesity, glaucoma, osteoporosis, cognitivedisorders, immune disorders, and depression

DISCLOSURE OF THE INVENTION

[0025] The compounds according to the present invention solve the aboveproblems and embraces a novel class of compounds which has beendeveloped and which inhibit the human 11-β-hydroxysteroid dehydrogenasetype 1 enyme (11-β-HSD1), and may therefore be of use in the treatingdisorders such as diabetes, obesity, glaucoma, osteoporosis, cognitivedisorders; immune disorders, and depression.

[0026] One object of the present invention is compound of formula (I)

[0027] wherein

[0028] T is

[0029] 1) thienyl which optionally is substituted with at least onehalogen, or

[0030] II phenyl substituted with

[0031] a) at least one C₂₋₆-alkyl; or

[0032] b) at least one C₁₋₆-alkyl and at least one halogen; or

[0033] c) at least three halogens;

[0034] E is a bond, —CH₂— or —CO—;

[0035] L is a bond, —CH₂—, —CHR⁴— or —NR³—;

[0036] R³ is H, C₁₋₆-alkyl C₁₋₆-acyl or —COR⁴;

[0037] R⁴ is morpholinyl or C₁₋₆ amido;

[0038] R⁶ and R⁷ are independently hydrogen or C₁₋₆-alkyl; and

[0039] R⁸ and R⁹ are independently hydrogen or C₁₋₆-alkyl as well aspharmaceutically acceptable salts, hydrates and solvates thereof

[0040] It is preferred that:

[0041] T is

[0042] I) thienyl, which is substituted with at least one halogenselected from cbloro and bromo, or

[0043] II) phenyl substituted with

[0044] a) at least one n-propyl; or

[0045] b) at least one methyl and at least one halogen selected fromchloro and bromo; or

[0046] c) at least three halogens selected from fluoro, bromo andchloro;

[0047] E is a bond, —CH₂— or —CO—;

[0048] L is a bond, CH₂—, —CHR⁴— or —NR³—;

[0049] R³ is methyl, acetyl or —COR⁴;

[0050] R⁴ is morpholinyl or propionamido;

[0051] R⁶ and R⁷ are both hydrogen; and

[0052] R⁸ and R⁹ are independently hydrogen or methyl.

[0053] Specific examples of compounds according to the present inventionare:N-(5-Acetyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4c]pyridin-2-yl)-3-chloro-2-methylbenzenesulfonamide;

[0054]2,4-dichloro-6-methyl-N-(5,6,6-tiimethyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzenesulf.onamide;

[0055]2,4-dichloro-6-methyl-N-[5-(4morpholinylcarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzenesulfonamide;

[0056]2,4-Dichloro-6-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;

[0057]4Bromo-N-(5,6-dihydro4H-cyclopenta[d][1,3]thiazol-2-yl)-2,5-difluorobenzenesulfonamide;

[0058] 2,3,4-Trichloro-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)benzenesulfonamide;

[0059]N-(2-{[(2,4-dichloro-6methylphenyl)sulfonylaminoo}4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide;

[0060]2,4-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-l,3-benzothiazol-2-yl)-6-methylbenzenesulfonamide;

[0061]2,3,4-Trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetydro-1,3-benzothiazol-2-yl)benzenesulfonamide;.

[0062]4,5-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonaeiide;

[0063]4-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazo1-2-yl)-2-thiophenesulfonanide;

[0064]3-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazo1-2-yl)-2-thiophenesulfonamide;

[0065]N-(5-Methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)4-propylbenzenesulfonamide;

[0066]4,5-Dichloro-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzotiazol-2-yl)-2-thiophenesulfonamide;

[0067]2,4-Dichloro-6-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamde;and

[0068]4-Bromo-2-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide.

[0069] Another object of the present invention is compound as describedabove for medical use.

[0070] The compounds as described above can be prepared by methodscomprising at least one of the following steps:

[0071] a) sulfonamide coupling by reacting a 2-aminothiazole with asulfonylcbloride in the presence of abase,

[0072] b) sulfonamide coupling by reacting a 2-aminothiazole derivativewith a sulfonylchloride in the presence of a base.

[0073] Another object of the present invention is a method for thetreatment or prevention of diabetes, syndrome X obesity, glaucoma,hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis,tuberculosis, dementia, depression, virus diseases and inflammatorydisorders, said method comprising administering to- a mammal, includingman, in need of such treatment, an effective amount of a compound havingthe formula (I)

[0074] wherein

[0075] T is I) thienyl which optionally is substituted with halogen, or

[0076] II) phenyl optionally substituted with halogen and/or C₁₋₆-alkyl;

[0077] E is a bond, —CH₂— or —CO—;

[0078] L is a bond, —CH₂—, —CHR⁴— or —NR³—;

[0079] R³ is H, C₁₋₆alkyl C₁₋₆-acyl or —COR⁴;

[0080] R⁴ is morpholino or C₁₋₆-amido;

[0081] R⁶ and R⁷ are independently hydrogen or C₁₋₆-allyl; and

[0082] R⁸ and R⁹ are independently hydrogen or C₁₋₆alkyl, as well aspharmaceutically acceptable salts, hydrates and solvates thereof.

[0083] These compounds may also be used in the manufacture of amedicament for the treatment or prevention of diabetes, syndrome Xobesity, glaucoma, hyperlipidemia, hyperglycemia, hypernsulinemia,osteoporosis, tuberculosis, dementia, depression, virus diseases andinflammatory disorders.

[0084] It is preferred that:

[0085] T is

[0086] I) thienyl which is substituted with at least one halogenselected from chloro and bromo, or

[0087] II) phenyl, which is substituted with at least one of methyln-propyl, fuoro, chloro and bromo;

[0088] E is a bond, —CH₂— or —CO—;

[0089] L is a bond, —CH₂—, —CHR⁴— or —NR³—;

[0090] R³ is methyl acetyl or —COR⁴;

[0091] R⁴ is morpholinyl or propionamido;

[0092] R⁶ and R⁷ are both hydrogen; and

[0093] R⁸ and R⁹ are independently hydrogen or methyl.

[0094] Specific examples of compounds according to the present inventionare given above.

[0095] Another object of the present invention is a pharmaceuticalcomposition comprising at least one compound of the formula (I) asdefined above, and a pharmaceutically acceptable carrier.

[0096] The compounds according to the present invention may be used inseveral indications which involve 11-β-hydroxysteroid dehydrogenase type1 enzyme. Thus the compounds according to the present invention may beused against dementia (see WO97/07789), osteoporosis (see Canalis E1996, Mechanisms of glucocorticoid action in bone: implications toglucocorticoid-induced osteoporosis, Journal of Clinical Endocrinologyand Metabolism, 81, 3441-3447) and may also be used disorders in theimmune system (see Franchimont et al, “Inhibition of Th1 immune responseby glucocorticoids: dexamethasone selectively inhibits IL 12-inducedStat 4 phosphorylation in T lymphocytes”, The journal of Immunology Feb15, 2000, vol 164 (4), pages 1768-74) and also in the above listedindications.

[0097] The various terms used, separately and in combinations, in theabove definition of the compounds having the formula (I) will beexplained.

[0098] The term “aryl” in the present description is intended to includearomatic rings (monocyclic or bicyclic) having from 6 to 10 ring carbonatoms, such as phenyl (Ph) and naphthyl, which optionally may besubstituted by C₁₋₆-allyl. Examples of substituted aryl groups arebezyl, and 2-methylphenyl.

[0099] The term “heteroaryl” means in the present description amonocyclic, bi- or tricyclic aromatic ring system (only one ring need tobe aromatic) having from 5 to 14, preferably 5 to 10 ring atoms such as5, 6, 7, 8, 9 or 10 ring atoms (mono- or bicyclic), in which one or moreof the ring atoms are other than carbon, such as nitrogen, sulfiw,oxygen and selenium Examples of such heteroaryl rings are pyrrole,imidazole, thiophene, A, thiazole, isothiazole, thiadiazole, oxazole,isoxazole, oxadiazole, pyridine, pyrazine, pyrimidine, pyridazine,pyrazole, tiazole, tetrazole, chroman, isochroman,qunolininoqulinoxaline, isoquinoline, phthalazine, cinnoline,quinazoline, indole, isoindole, indoline, isoindoline, benzothiophene,benzofurau, isobenzofuran, benzoxazole, 2,1,3-benzoxadiazole,benzothiazole, 2,1,3-benzothiazole, 2,1,3-benzoselenadiazole,benzimidazole, indazole, benzodioxane, indane,1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine,1,5-naphthyridine, 1,8-naphthyridine, acridine, fenazine and xanthene.

[0100] The term “heterocyclic” in the present description is intended toinclude unsaturated as well as partially and fully saturated mono-, bi-and tricyclic rings having from 4 to 14, preferably4 to 10 ring atoms,such as, for example, the heteroaryl groups mentioned above as well asthe corresponding partially saturated or fully saturated heterocyclicrings. Exemplary saturated heterocyclic rings are azefidine,pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine and1,4-oxazepane.

[0101] C₁₋₆-alkyl in the compound of formula (I) according to thepresent application, which may be straight, branched or cyclic, ispreferably C₁₋₄-allyl. Exemplary alkyl groups include methyl, ethyl,n-propyl isopropyl n-butyl, sec-butyl tert-butyl, pentyl isopentyl,hexyl isohexyl and cyclohexyl.

[0102] C₂₋₆-alkyl in the compound of formula (I) according to thepresent application, which may be straight, branched or cyclic, ispreferably C₂₋₄-alkyl. Exemplary alkyl groups include ethyl, u-propyl,isopropyl n-butyl sec-butyl, tert-butyl pentyl, isopentyl, hexylisohexyl, and cyclohexyl.

[0103] C₁₋₆-acyl, in the compound of formula (I) according to tlhepresent application may be saturated or unsaturated and is preferablyC₁₋₄-acyl. Exemplary acyl groups include formyl, acetyl propionylbutyryl, isobutyryl, valeryl isovaleryl, butenoyl (e.g. 3-butenoyl),hexenoyl (e.g. 5-hexenoyl).

[0104] C₁₋₆-amido, in the compound of formula (I) according to thepresent application may be saturated or unsaturated and is preferablyC₁₋₄-amido. Exemplary amido groups include formamido, acetamido,propionamido, butyramido, isobutyramido, valeramido, isovaleramido,butenamido (e.g. 3-butenamido), hexenamido (e.g. 5-hexenamido).

[0105] The term “halogen” in the present description is intended toinclude fluorine, chlorine, bromine and iodine.

[0106] With the expression mono- or di-substituted is meant in thepresent description that the fimctionalities in question may besubstituted with independently H, C₁₋₆-acyl, C₁₋₆-alkenyl,C₁₋₆-(cyclo)allcyl, aryl pyridylmethyl, or heterocyclic rings e.g.azetidine, pyrrolidine, piperidine, piperazine, morpholine andthiomorpholine, which heterocyclic rings optionally may be substitutedwith C₁₋₆-alkyl.

[0107] The term “prodrug forms” in the present description means apharmacologically acceptable derivative, such as an ester or an amide,which derivative is biotransformed in the body to form the active drug(see Goodman and Gilman's, The Pharmacological basis of Therapeutics,8^(th) ed., McGraw-Hill, Int. Ed. 1992, “Biotransformation of Drugs, p.13-15).

[0108] “Pharmaceutically acceptable” means in the present descriptionbeing useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable andincludes being useful for veterinary use as well as human pharmaceuticaluse.

[0109] “Pharmaceutically acceptable salts” mean in the presentdescription salts which are pharmaceutically acceptable, as definedabove, and which possess the desired pharmacological activity. Suchsalts include acid addition salts formed with organic and inorganicacids, such as hydrogen chloride, hydrogen bromide, hydrogen iodide,sulffric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid,malonic acid, oxalic acid, methanesulfonic acid, truoroacetic acid,finmaric acid, succinic acid, tartic acid, citric acid, benzoic acid,ascorbic acid and the like. Base addition salts may be formed withorganic and inorganic bases, such as sodium, ammonia, potassium calcium,ethanolamine, diethanolamine, N-methylglucamine, choline and the like.

[0110] Pharmaceutical compositions according to the present inventioncontain a pharmaceutically acceptable carrier together with at least oneof the compounds comprising the formula (I) as described herein above,dissolved or dispersed therein as an active, antimicrobial, ingredient.In a preferred embodiment, the therapeutic composition is notimmunogenic when administered to a human patient for therapeuticpurposes, unless that purpose is to induce an imune response.

[0111] The preparation of a pharmacological composition that containsactive ingredients dissolved or dispersed therein is well understood inthe art Typically such compositions are prepared as sterile injectableseither as liquid solutions or suspensions, aqueous or non-aqueous,however, solid forms suitable for solution, or suspensions, in liquidprior to use can also be prepared The preparation can also beemulsified.

[0112] The active ingredient may be mixed with excipients, which arepharmaceutically acceptable and compatible with the active ingredientand in amounts suitable for use in the therapeutic methods describedherein. Suitable excipients are, for example, water, saline, dextrose,glycerol, ethanol or the like and combinations thereof. In addition, ifdesired, the composition may contain minor amounts of vary substancessuch as wetting or emulsifying agents, pH buffering agents and the likewhich enhance the effectiveness of the active ingredient. Adjuvants mayalso be present in the composition.

[0113] Pharmaceutically acceptable carriers are well known in the artExemplary of liquid carriers are sterile aqueous solutions that containno materials in addition to the active ingredients and water, or containa buffer such as sodium phosphate at physiological pH value,physiological saline or both, such as phosphate-buffered saline. Stillfurther, aqueous carriers can contain more than one buffer salt, as wellas salts such as sodium and potassium chlorides, dextrose, propyleneglycol, polyethylene glycol and other solutes.

[0114] Liquid compositions can also contain liquid phases in addition toand to the exclusion of water. Exemplary of such additional liquidphases are glycerine, vegetable oils such as cottonseed oil, organicesters such as ethyl oleate, and water-oil emulsions.

[0115] The pharmaceutical composition according to one of the preferredembodiments of the present invention comprising compounds comprising theformula (I), may include pharmaceutically acceptable salts of thatcomponent therein as set out above. Pharmaceutically acceptable saltsinclude the acid addition salts (formed with the free amino groups ofthe polypeptide) that are formed with inorganic acids such as, forexample, hydrochloric or phosphoric acids, or such organic acids asacetic acid, tartaric acid, mandelic acid and the like. Salts formedwith the free carboxyl groups can also be derived from inorganic basessuch as, for example, sodium, potassium, ammonium, calcium or ferrichydroxides, and such organic bases as isopropylamine, timethylamine,2-ethylamino ethanol, histidine, procaine and the like.

[0116] The preparations according to the preferred embodiments may beadministered orally, topically, intraperitoneally, intraarticularly,intracranially, intradermally, intramuscularly, intraocularly,intrathecally, intravenously, subcutaneously. Other routes which arekiown for the skilled person in the art are thiable.

[0117] The orally administrable compositions according to the presentinvention may be in the form of tablets, capsules, powders, granules,lozenges, liquid or gel preparations, such as oral, topical or sterileparenteral solutions or suspensions. Tablets and capsules for oraladministration may be in unit dose presentation form and may containconventional excipients such as binding agents, for example syrup,acacia, gelatin, sorbitol, traganath or polyvinyl-pyrrolidone; fillerse.g. lactose, sugar, maize-starch, calcium phosphate, solbitol orglycine; tabletting lubricant e.g. magnesium stearate, talc,polyethylene glycol or silica; disintegrants e.g. potato starch, oracceptable wetting agents such as sodium lauryl sulfate. The tablets maybe coated according to methods well known in normal pharmaceuticalpractice. Oral liquid preparations may be in the form of e.g. aqueous oroily suspensions, solutions, emulsions, syrups or elicirs or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, e.g. sorbitol, syrup,methyl cellulose, glucose syrup, gelatin hydrogenated edible fats;emulsffying agents e.g. lecithin, sorbitan monooleate or acacia,non-aqueous vehicles (which may include edible oils), e.g. almond oil,fractionated coconut oil, oily esters such as glycerine, propyleneglycol or ethyl alcohol; preservatives e.g. methyl or propylp-hydroxybenzoate or sorbic acid, and if desired conventional flavouringor colouring agents.

[0118] A pharmaceutical composition according to the present invention,may comprise typically an amount of at least 0.1 weight percent ofcompound comprising the formula (I) per weight of total therapeuticcomposition. A weight percent is a ratio by weight of total composition.Thus, for example, 0.1 weight percent is 0.1 grams of compoundcomprising the formula (I) per 100 grams of total composition. Asuitable daily oral dose for a mammal preferably a human being, may varywidely depending on the condition of the patient. However a dose ofcompound comprising the formula (I) of about 0.1 to 300 mglkg bodyweight may be appropriate.

[0119] The compositions according to the present invention may also beused veterinarily and thus they may comprise a veterinarily acceptableexcipient or carrier.

[0120] The compounds of the present invention in labelled form, e.g.isotopically labelled, may be used as a diagnostic agent.

[0121] The compounds of the formula (I) above may be prepared by, or inanalogy with, conventional methods, and especially according to or inanalogy with the following methods. Further, the pharmacology in-vitrowas studied using the following reagents and methods.

[0122] All publications mentioned herein are hereby incorporated byreference. By the expression “comprising” we understand including butnot limited to. Thus, other non-mentioned substances, additives orcarriers may be present.

[0123] The invention will now be described in reference to the followingFigures and Examples. These Figures and Examples are not to be regardedas limiting the scope of the present invention, but shall only serve inan illustrative manner.

[0124] Experimental Methods

[0125] Scintillation Proximity Assay

[0126] [1,2(n)-³H]-cortisone was purchased from Amersham PharmaciaBiotech. Anti-cortisol monoclonal mouse antibody, clone 6D6.7 wasobtained from Immunotech and Scintillation proximity assay (SPA) beadscoated with monoclonal antimouse antibodies were from Amersham PharmaciaBiotech. NADPH, tetrasodium salt was from Calbiochem andglucose-6-phosphate (G-6-P) was supplied by Sigma The human11-β-hydroxysteroid dehydrogenase type-i enzyme (11-β-HSD₁) wasexpressed in Pichia pastoris. 18-β-glycyrhetinic acid (GA) was obtainedfrom Sigma. The serial dilutions of the compounds were performed on aTecan Genesis RSP 150. Compounds to be tested were dissolved in DMSO (1mM) and diluted in 50 mM Tris—HCl, pH 7.2 containing 1 mM EDTA

[0127] The multiplication of plates was done on a WallacQuadra. Theamount of the product [³H]-cortisol, bound to the beads was determinedin a Packard, Top Count microplate liquid scintillation counter.

[0128] The 11-β-HSD₁ enzyme assay was carried out in 96 well microtiterplates (Packard, Optiplate) in a total well volume of 220 μL andcontained 30 mM Tris—HCl pH 7.2 with 1 mM EDTA, a substrate mixturetritiated Cortisone/NADPH (175 nM/181 μM, G-6-P (1 mM) and inhibitors inserial dilutions (9 to 0.15 μM. Reactions were initiated by the additionof human 11-β-HSD₁, either as Pichia pastoris cell homogenate ormicrosomes prepared from Pichia pastoris (the final amount of enzymeused was varied between 0.057 to 0.11 mg/mL). Following mixing, theplates were shaken for 30 to 45 minutes at room temperature. Thereactions were terminated with 10 μL 1 mM GA stop solution. Monoclonalmouse antibody was then added (10 μL of 4 μM) followed by 100 μL of SPAbeads (suspended according to the manufacturers instructions).Appropriate controls were set up by omitting the 11-β-HSD₁ to obtain thenon-specific binding (NSB) value.

[0129] The plates were covered with plastic film and incubated on ashaker for 30 minutes, at room temperature,. before counting. The amountof [³H]-cortisol, bound to the beads was determined in a microplateliquid scintillation counter.

[0130] The calculation of the K; values for the inhibitors was performedby use of Activity Base. The K_(i) value is calculated from IC₅₀ and theK_(m) value is calculated using the

[0131] Cheng Pnishoff equation (with reversible inhibition that followsthe Michaelis-Menten equation): K_(i=IC) ₅₀(1+[S]/K_(m)) [Cheng, Y. C.;Pnishoff, W. H. Biochem. Pharmacol. 1973, 22, 3099-3108]. The IC₅₀ ismeasured experimentally in an assay wherein the decrease of the turnoverof cortisone to cortisol is dependent on the inhibition potential ofeach substance. The Ki values of the compounds of the present inventionfor the 11-β-HSD1 enzyme lie typically between about 10 nM and about 10μM. Illustrative of the invention, the following Ki values have beendetermined in the human 11-β-HSD1 enzyme assay (see Table 1): TABLE 1 Kivalues determined in the human 11-β-HSD1 enzyme assay. Compound ofExample K_(i) (nM) 8 28 16 227

[0132] Compound Preparation

[0133] General:

[0134] For preparative straight phase HPLC purification a Phenomenexcolumn (250×21.1 mm, 10 μm) was used on a Gilson system eluting withethanol in chloroform (gradient from 0-10% in 10 min) with a flow of 20mL/min. Column chromatography was performed on silica using Silica gel60 (230-400 mesh), Merck. Melting points were determined on a Gallenkampapparatus. Elemental analyses were recorded using a Vario EL instrument.HPLC analyses were performed using a Hypersil Elite column (150×4.6 mm,3μ) with a flow of 3 mL/min on a Waters 600E system with monitoring at254 nm Reverse phase preparative HPLC was carried out on a 100×21.2 mm,5μ Hypersil Elite column eluting with a gradient of 5% ACN in 95% waterto 95% ACN in 5% water (0.2% TFA buffer) over 10 mins at a flow rate of20 mL/min with the UV detector set at 254 nm. Thin layer chromatographywas carried out using pre-coated silica gel F-254 plates (thickness 0.25mm). Electrospray MS spectra were obtained on a Micromass platform LCMSspectrometer. Cride, worked up compounds were purified by flash columnchromatography using pre packed silica SPE columns (10 g silica) on anIsco Foxy 200 Combiflash system, and a gradient of 16.67% ethyl acetatein hexane increasing incrementally to 100% ethyl acetate.

[0135] List of Abbreviations

[0136] DCM=dichloromethane

[0137] DMAP=4-dimethylaminopyridine

[0138] DMF=dimethylfonmamide

[0139] DMSO=dimethyl sulfoxide

[0140] EDTA=ethylenediaminetetraacetic acid

[0141] Sulfonamide Couplings:

[0142] Method A:

[0143] 1 Eq of the 2-aminothiazole was dissolved in pyridine (0.5 Msolution). The sulfonyl chloride (1.2 eq) was added and the reactionmixture was stirred at ambient temperature under nitrogen atmosphere for15 h. The reaction mixture was poured into aqueous HCl (1 M). If theproduct precipitated it was collected on a filter and washed withaqueous HCl (1 M) and recrystalised from ethanol. In case an oil wasobtained, the crude was extracted with DCM and worked up and purifiedusing standard procedures.

[0144] Method B:

[0145] A solution of the 2-aminothiazole derivative (1 eq),triethylamine (2 eq) and DMAP (1 eq) in DMF (1 M) and DCM (0.225 ND wasdispensed into a reaction vial. The sulfonyl chloride (1.2 eq) wasdissolved in DCM (0.33 M) and added. The reaction mixtures were kept atroom temperature over night. The mixte was then added to petroleum ether(10 times reaction volume). After some hours in refrigerator thesupernatants were decanted and (a portion of) the residual materialswere dissolvedin DMSO-methanol-acetic acid (300 μL+500 μL+50 μL) andpurified by preparative LCMS (acetonitrile-water gradients). The purestfractions were collected and lyophilized. Alteriatively? the crude wasisolated using extractive work-up and purified using standardprocedures.

EXAMPLES

[0146] The following specific compounds were synthesized. Thecommercially available compounds thus only form embodiments, asindicated earlier in the description, as pharmaceutical compositions anduse of said compounds as set out in the appended set of claims.

Example 1

[0147] [210P]

[0148]N-(5-Acetyl-4,5,697-tetrahydro[193]thiazolo[5,4cJpyridin-2-yl)-3-chioro-2-methylbenzenesulfonamide

[0149] N-Acetyl4-piperidone (7.05 g, 0.05 mol) in acetic acid (35 mL)was treated dropwise with bromine (8.0 g, 0.05 mol) in acetic acid (10mL) at room temperature. After 4 h, the formed precipitate was collectedon a filter, washed with diethyl ether and air-dried. This crudeintermediate (3.01 g) was dissolved in ethanol (20 mL) and after theaddition of thiourea (0.76 g, 10.0 mmol)the reaction mixture wasrefiuxed for 4 h. The solvent was removed in vacuo. Water (20 mL) wasadded and the pH was adjusted to 9. Extraction with DCM, drying (sodiumsulfate) and removal of the organic phase gave 1.1 g of a crude product.Modification by flash chromatography on silica gel gave 202 mg (10%) of5-acetyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-ylamine. Thiscompound was sulfonylated with 3-chloro-2-methylbenzene sulfonylchloride (234 mg, 1.02 mmol) in pyridine according to METHOD A. Afterworkup, the final product was crystallised from methanol to afford 75 mg(%) of white crystals: ¹H NMR (DMSO-d₆, 70° C.) δ 2.05 (s, 3H), 2.66 (s,3H), 3.09 (m, 2H), 3.69 (m, 2H), 4.38 (m 2H), 7.37 (t 1H), 7.64 (L, 1H),7.91 (d, 1H), 12.53 (br s, NH).

Example 2

[0150] [211A]

[0151]2,4-dichloro-6methyl-N-(5,6,6-trimethyl-4,5,6,7-tetrahydro[113]thiazolo[5,4c]pyridin-2-yl)benzenesulfonamide

[0152] The title compound was prepared from5,6,tridmethyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4c]pyridin-2-anie (45mg, 0.23 mmol) as described in the synthetic METHOD B to give a whitesolid (13.0 mg) with pnrity >90%. MS (pos) m/z 420.1, 422.1.

Example 3

[0153] [212A]

[0154]2,4-dichloro-6-methyl-N-[5-(4morpholinylcarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4]pyridin-2-yl]benzenesulfonamide

[0155] The title compound was prepared from5-(4morpholinylcarbonyl)4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-amine(39 mg, 0.15 mmol) as described in the synthetic METHOD B to give ayellow solid (15.4 mg) with purity >⁹⁰%. MS (pos) m/z491.1, 493.1.

Example 4

[0156] [234A]

[0157]2,4-Dichloro-6methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide

[0158] The title compound was prepared from4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine as described in thesynthetic METHOD B to give a white solid (10.8 mg) with purity >90%. MS(pos) m/z 377.1, 379.1.

Example 5

[0159] [234B]

[0160]4-Bromo-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl2,5-difluorobenzenesulfonamide

[0161] The title compound was prepared from2-amino-5,6-dihydro4H-cyclopentathiazole hydrochloride (48 mg) and4-bromo-2,5-difluorobenzenesulfonyl chloride (79 mg) as described in thesynthetic METHOD B to give a yellow solid (2.5 mg) with purity >80%. MS(pos) m/z 395.2, 397.2; MS (neg) m/z 393.4, 395.4.

Example 6

[0162] [234C]

[0163]2,3,4-Trichloro-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)benzenesulfonamide

[0164] The title compound was prepared from2-amino-5,6-dihydro-4H-cyclopentathiazole hydrochloride (48 mg) and2,3,4tichlorobenzenesulfonyl chloride (76 mg) as described in thesynthetic METHOD B to give a yellow solid (4.5 mg): MS (pos) m/z 383.3,385.3, 387.3; MS (neg) m/z 381.4, 383.4, 385.4.

Example 7

[0165] [235A]

[0166]N-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-4,5,6,7-tetrahydro1,3-benzothiazol-6-yl)propanamide

[0167] The title compound was prepared fromN-(2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide (47 mg,0.21 mmol) and 2,4-dichloro-6-methylbenzenesulfonyl chloride asdescribed in the synthetic METHOD B to give a white solid (20.3 mg) withpurity >90%. MS (pos) m/z 448.1, 450.1.

Example 8

[0168] [236A]

[0169]2.4-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazo1-2-yl)-6methylbenzenesulfonamide

[0170] The title compound was prepared from 2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one hydrobromide and2,4-dichloro-6-methylbenzenesulfonyl chloride as described in thesynthetic METHOD B to give a white-yellow solid (26 mg) withpurity >90%: MS (pos) m/z 419.1, 421.1; HRMS m/z 417.9979 (calc. ofmonoisotopic mass for C₁₆H₁₆Cl₂N₂O₃S₂ gives 417.9979).

Example 9

[0171] [236B]

[0172]2,3,4-Trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide

[0173] The title compounid was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and2,3,4-trichlorobenzenesulfonyl chloride (76 mg) as described in thesynthetic METHOD B to give a white solid (47.2 mg) with purity >90%: MS(pos) m/z 439.3, 441.3; HRMS m/z 437.9451 (calc. of monoisotopic massfor C₁₅H₁₃Cl₃N₂O₃S₂ gives 437.9433).

Example 10

[0174] [236C]

[0175]4,5Dichloro-N-(5,4dimethyl-7-oxo-4,5,6,7-tetrahydro1,3-benzothiazo1-2-yl)2-thiophenesulfonamide

[0176] The title compound was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and2,3-dichlorotiophene-5-sulfonyl chloride (68 mg) as described in thesynthetic METHOD B to give a white-yellow solid (36.8 mg) withpurity>90%: MS (pos)m/z411.3, 413.3.

Example 11

[0177] [236D]

[0178]4-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide

[0179] The title compound was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)one (53 mg) and4-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described inthe synthetic METHOD B to give a white-yellow solid (47.1 mg) withpurity >90%: MS (pos) m/z 455.2, 457.2.

Example 12

[0180] 236E]

[0181]3-Bromo-5chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)2-thiophenesulfonamide

[0182] The title compound was prepared from2-amino-5,5-dimethyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (53 mg) and3-bromo-5-chlorothiophene-2-sulfonyl chloride (80 mg) as described inthe synthetic method to give a white solid (62.2 mg) with purity >90%:MS (pos) m/z 455.2, 457.2.

Example 13

[0183] [236F]

[0184]N-(5-Methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-4-propylbenzenesulfonamide

[0185] The title compound was prepared from2-amino-5-methyl-5,6-dihydro-1,3-benzotliazol-7(4H)one (49 mg) and4-n-propylbenzenesulfonyl chloride (59 mg) as described in the syntheticMETHOD B to give a white solid (51.2 mg) with purity >90%: MS (neg) m/z363.6; HRMS m/z 364.0911 (calc. of monoisotopic mass for C₁₇H₂₀Cl₅N₂O₃S₂gives 364.0915).

Example 14

[0186] [236G]

[0187]4,5-Dichloro-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide

[0188] The title compound was2-amiino-5-methyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (49 mg) and2,3-dichlorothiophene-5-sulfonyl chloride (68 mg) as described in thesynthetic METHOD B to give a white solid (34.2 mg) with purity >90%: MS(pos) m/z 397.2, 399.2; MS (neg) m/z 395.2, 397.2.

Example 15

[0189] [236H]

[0190]2.4-Dichloro-6-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazo1-2-yl)benzenesulfonamide

[0191] The title compound was2-amino-5-methyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one (49 mg) and2,4-dichloro-6-methylbenzenesulfonyl chloride (70 mg) as described inthe synthetic METHOD B to give a white solid (39.3 mg) with purity >90%:MS (pos) m/z 405.4, 407.4; MS (neg) m/z 403.4, 405.3.

Example 16

[0192] [236I]

[0193]4Bromo-2methyl-N-(5methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide

[0194] The title compound was2-amino-5-methyl-5,6-dihydro-1,3-benzothiazol-7(4H)-one. (49 mg) and4-bromo-2-methylbenzenesulfonyl chloride (73 mg) as described in thesynthetic METHOD B to give a white solid (34.4 mg) with purity >90%: MS(pos) m/z 415.4, 417.4; MS (neg) m/z 413.4, 415.4.

[0195] Various embodiments of the present invention have been describedabove but a person skilled in the art realizes further minor alterationswhich would fall into the scope of the present invention. The breadthand scope of the present invention should not be limited by any of theabove-described exemplary embodiments, but should be defined only inaccordance with the following claims and their equivalents.

1. A compound according to the formula (I)

wherein T is I) thienyl, which optionally is substituted with at leastone halogen, or II) phenyl substituted with a) at least one C₂₋₆-allyl;or b) at least one C₁₋₄-alkyl and at least one halogen; or c) at leastthree halogens; E is a bond, —CH₂— or —CO—; L is a bond, CH₂—, —CHR⁴— orNR³—; R³ is H, C₁₋₆-alkyl, C₁₋₆-acyl or —COR⁴; R⁴ is morpholinyl or C₁₋₆amindo; R⁶ and R⁷ are independently hydrogen or C₁₋₆-allyl; and R⁸ andR⁹ are independently hydrogen or C₁₋₆-alkyl, as well as pharmaceuticallyacceptable salts, hydrates and solvates thereof:
 2. A compound accordingto claim 1, wherein T is I) thienyl, which is substituted with at leastone halogen selected from cbloro and bromo, or II) phenyl substitutedwith a) at least one n-propyl; or b) at least one methyl and at leastone halogen selected from chloro and bromo; or c) at least threehalogens selected from fluoro, bromo and chloro; E is a bond, —CH₂— or—CO—; L is a bond, —CH₂—, —CHR⁴— or —NR³—; R³ is methyl, acetyl or—COR⁴; R⁴ is morpholinyl or propionamido; R⁶ and R⁷ are both hydrogen;and R⁸ and R⁹ are independently hydrogen or methyl.
 3. A compoundaccording to claim 1-2, selected from the group of:N-(5-Acetyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3chloro-2-methylbenzenesulfonyl;2,4-dichloro-6-methyl-N-(5,6,6-tiimethyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzenesulfonamide;2,4-dichloro-6-methyl-N-[5-(4-morpholinylcarbonyl)4,5,6,7-tetrahydro[1,3]thiazolo[5,4c]pyridin-2-yl]benzenesulfonamide;2,4-Dichloro-6-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;4-Bromo-N-(5,6-dihydro4H-cyclopenta[d][1,3]thiazol-2-yl)-2,5-difluorobenzenesulfonamide;2,3,4-Trichloro-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)benzenesulfonamide;N-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}4,5,6,7-tetrahydro1,3-benzothiazol-6-yl)propanamide;2,4Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-6-methylbenzenesulfonamide;2,3,4Trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;4,5-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)2-thiophenesulfonamide;4-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)2-thiophenesulfonamide;3-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;N-(5-Methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)4-propylbenzenesulfonamide;4,5-Dichloro-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;2,4-Dichloro-6-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;and4-Bromo-2-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide.4. A compound according to anyone of claims 1-3, for medical use.
 5. Aprocess for the preparation of a compound according to claim 1-3composing at least one of the following steps: a) sulfonamide couplingby reacting a 2-aminothiazole with a sulfonylchloride in the presence ofa base, b) sulfonamide coupling by reacting a 2-aminothiazole derivativewith a sulfonylchloride in the presence of a base.
 6. A method for thetreatment-or prevention of diabetes, syndrome Y, obesity, glaucoma,hyperlipidemia, hyperglycemia, hyperinsulinemia, osteoporosis,tuberculosis, dementia, depression, virus diseases and inflammatorydisorders, said method comprising administering to a mammal, includingman, in need of such treatment, an effective amount of a compound havingthe formula (I)

wherein T is I) thienyl which optionally is substituted with halogen, orII) phenyl optionally substituted with halogen and/or C₁₋₆-alkyl; E is abond, —CH₂— or —CO—; L is a bond, —CH₂—, —CHR⁴— or —NR³—; R³ is H,C₁₋₆-alkyl, C₁₋₆-acyl or —COR⁴; R⁴ is morpholino or C₁₋₆-amido; R⁶ andR⁷ are independently hydrogen or C₁₋₆-alkyl; and R⁸ and R⁹ areindependently hydrogen or C₁₋₆-alkyl, as well as pharmaceuticallyacceptable salts, hydrates and solvates thereof.
 7. A method accordingto claim 6, wherein T is I) thienyl, which is substituted with at leastone halogen selected from chloro and bromo, or II) phenyl, which issubstituted with at least one of methyl n-propyl, fluoro, chloro andbromo; E is a bond, —CH₂— or —CO—; L is a bond, —CH₂—, —CHR⁴— or —NR³—;R³ is methyl acetyl or —COR⁴; R⁴ is morpholinyl or propionamido; R⁶ andR⁷ are both hydrogen; and R⁸ and R⁹ are independently hydrogen ormethyl.
 8. A method according to claim 6-7, wherein the compound isselected from the group of:N-(5-Acetyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-chloro-2-methylbenzenesulfonamide;2,4-dichloro-6-methyl-N-(5,6,6-trimethyl-4,5,6,7-tetrahydro[l1,3]thiazolo[5,4-c]pyridin-2-yl)benzenesulfonamide;2,4-dichloro-6-methyl-N-[5-(4-morpholinylcarbonyl)4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzenesulfonamide;2,4-Dichloro-6.-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;4-Bromo-N5,6-dihydro4H-cyclopenta[d][1,3]thiazol-2-yl)-2,5-difluorobenzenesulfonamide;2,3,4-Trichloro-N-(5,6-dihydro-4H-cyclopenta[d][1,3Thiazol-2-yl)benzenesulfonamide;N-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide;2,4-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-6-methylbenzenesulfonamide;2,3,4-Trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;4,5-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;4-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonaeiide;3-Bromo5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;N-(5-Methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)4-propylbenzenesulfonamide;4,5-Dichloro-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;2,4Dichloro-6-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazo1-2-yl)benzenesulfonamide;and4-Bromo-2-methyl-N5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide.9. The use of a compound having the formula (I)

wherein T is I) thienyl, which optionally is substituted with halogen,or II) phenyl optionally substituted with halogen and/or C₁₋₆-alkyl; Eis a bond, —CH₂— or —CO—; L is a bond, —CH₂—, —CHR⁴— or —NR³—; R³ is H,C₁₋₆-alkyl, C₁₋₆-acyl or —COR⁴; R⁴ is morpholino or C₁₋₆-amido; R⁶ andR⁷ are independently hydrogen or C₁₋₆-alkyl; and R⁸ and R⁹ areindependently hydrogen or C₁₋₆-alkyl, as well as pharmaceuticallyacceptable salts, hydrates and solvates thereof, in the manufacture of amedicament for the treatment or prevention of diabetes, syndrome Xobesity, glaucoma, hyperlipidemia, hyperglycemia, hyperinsulinemia,osteoporosis, tuberculosis, dementia, depression, virus diseases andinflammatory disorders.
 10. A method according to claim 9, wherein T isI) thienyl, which is substituted with at least one halogen selected fromchloro and bromo, or II) phenyl, which is substituted with at least oneof methyl n-propyl, fluoro, chloro and bromo; E is a bond, —CH₂— or—CO—; L is a bond, —CH₂—, —CHR⁴— or —NR³—; R³ is methyl acetyl or —COR⁴;R⁴ is morpholinyl or propionamido; R⁶ and R⁷ are both hydrogen; and R⁸and R⁹ are independently hydrogen or methyl.
 11. A method according toclaim 9-10, wherein the compound is selected from the group of:N-(5-Acetyl4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-chloro-2-methylbenzenesulfonamide;2,4-dichloro-6-methyl-N5,6,6-trimethyl4,5,6,7-tetrahydro1,3]thiazolo5,4-c]pyridin-2-yl)benzenesulfonamide;2,4dichloro-6-methyl-N-[5-(4-morpholinylcarbonyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4c]pyridin-2-yl]benzenesulfonamide;2,4-Dichloro-6-methyl-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;4-Bromo-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)-2,5-difluorobenzenesulfonamide;2,3,4-Trichloro-N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)benzenesulfonamide;N-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino}-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl)propanamide;2,4Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-6-methylbenzenesulfonamide;2,3,4-Trichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;4,5-Dichloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;4-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;3-Bromo-5-chloro-N-(5,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazo1-2-yl)-2-thiophenesulfonanide;N-(5-Methyl-7oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)4-propylbenzenesulfonamide;4,5-Dichloro-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-2-thiophenesulfonamide;2,4-Dichloro-6-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzenesulfonamide;and4-Bromo-2-methyl-N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-1,3-benzotliazol-2-yl)benzenesulfonamide.12. A pharmaceutical composition comprising at least one compoundaccording to anyone of claims 1-3, and a pharmaceutically acceptablecarrier.